Azacitidine to Consolidate and Deepen the Therapeutic Response Achieved by Intensive Induction Treatment in a Young Patient Affected by NPM1mut-AML Who Has Become Ineligible for High-Dose Consolidation

Chemotherapy ◽  
2022 ◽  
pp. 1-5
Author(s):  
Natalia Cenfra ◽  
Gianfranco Lapietra ◽  
Salvatore Perrone ◽  
Maria Teresa Voso ◽  
Mariadomenica Divona ◽  
...  
Keyword(s):  
Young Patient ◽  
Residual Disease ◽  
Therapeutic Option ◽  
Young Patients ◽  
Low Risk ◽  
Induction Treatment ◽  
High Dose ◽  
Npm1 Mutation ◽  
Effective Therapeutic Option ◽  
Molecular Landscape

Acute myeloid leukemia (AML) is the most common leukemia in adults. In spite of the most recent discoveries about the molecular landscape of this disease, the treatment of elderly and unfit young patients continues to be a great challenge. The hypomethylating agents (HMA) still represent an effective therapeutic option for these categories, especially for the low-risk subgroups. We report the case of a young patient with NPM1<sup>mut</sup>-AML who underwent a first cycle of intensive induction treatment, achieving a complete remission, but suffered from a serious life-threatening neurologic toxicity. Due to the ineligibility to further lines of intensive chemotherapy, we decided to consolidate the response with azacitidine, administered according to the regular schedule. The minimal residual disease (MRD), monitored through the NPM1 mutation at diagnosis, progressively decreased and became undetectable after 36 cycles of hypomethylating therapy. After 1 year from discontinuation of azacitidine, MRD remains undetectable. Therefore, HMA might still represent a feasible and effective option for patients with low-risk AML, especially when the standard chemotherapy is not indicated, or as maintenance therapy in nontransplantable patients.

Does interleukin-2 have a role in the management of acute leukemia?

1993 ◽  
Vol 11 (9) ◽  
pp. 1817-1825 ◽  
Author(s):  
R Foa
Keyword(s):  
Acute Leukemia ◽  
Residual Disease ◽  
Therapeutic Option ◽  
Interleukin 2 ◽  
Leukemia Cell ◽  
Retroviral Vectors ◽  
High Dose ◽  
Functional Changes ◽  
Leukemia Cell Lines ◽  
Infusion Protocol

PURPOSE To discuss the possibility that interleukin-2 (IL-2)-based immunotherapeutic protocols may have a role in the management of acute leukemia. DESIGN The preclinical results that have led to the clinical use of IL-2 in acute leukemia will be reviewed. The clinical data obtained with the administration of IL-2 to acute leukemia patients in different phases of their disease will be discussed, together with the clinicohematologic and immunologic modifications induced following the infusion of IL-2. Finally, the possibility that limitations associated with the exogenous administration of high-dose IL-2 may be circumvented by engineering techniques aimed at inserting the IL-2 gene directly into the tumor cells, will be addressed. RESULTS The data indicate that high-dose IL-2 may be administered to acute leukemia patients. Toxicity, recorded in all patients, appears to be controllable using a continuous intravenous (i.v.) infusion protocol based on a daily dose-escalating administration. Complete remissions have been documented in acute myeloid leukemias (AMLs) with a limited, but detectable proportion of residual marrow blasts. Numerous phenotypic and functional changes have been recorded within the immune system of the host. Using retroviral vectors, the IL-2 gene may be productively transduced into human acute leukemia cell lines. CONCLUSION IL-2 appears to represent a therapeutic option for AML patients with limited/minimal residual disease. The results of the ongoing randomized trials in patients in first or second remission are awaited.

scholarly journals Stereotactic Radiosurgery Associated Neurotoxicity

2003 ◽  
Vol 2 (2) ◽  
pp. 147-151 ◽  
Author(s):  
William H. St. Clair ◽  
Curtis A. Given
Keyword(s):  
Stereotactic Radiosurgery ◽  
Therapeutic Option ◽  
Treatment Plan ◽  
Three Dimensional ◽  
Reference Points ◽  
Therapeutic Modality ◽  
High Dose ◽  
Lesion Volume ◽  
Three Dimensional Mapping ◽  
Effective Therapeutic Option

Stereotactic radiosurgery (SRS) is an evolving therapeutic modality for well demarcated intracranial lesions. Since the inception of stereotactic radiosurgery the types of parenchymal CNS lesions addressed by this mode of treatment has increased. All modern stereotactic radiosurgical procedures employ several common features. Patients are fitted with a stereotactic head frame or fiducial markers followed by radiographic imaging which allows for external reference points and three-dimensional mapping of the intracranial lesion. Armed with this information a highly conformal treatment plan is developed to deliver a high dose of radiation to a sharply defined target, with rapid dose fall-off outside the lesion volume. While an extremely effective therapeutic option, SRS is not without risk of neurotoxicity, with radiation necrosis being the most commonly recognized complication. The neurotoxic effects of SRS are reviewed and discussed.

Adding The KIT Inhibitor Dasatinib (DAS) To Standard Induction and Consolidation Therapy For Newly Diagnosed Patients (pts) With Core Binding Factor (CBF) Acute Myeloid Leukemia (AML): Initial Results Of The CALGB 10801 (Alliance) Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 357-357 ◽  
Author(s):  
Guido Marcucci ◽  
Susan Geyer ◽  
John Zhao ◽  
Andrew J Caroll ◽  
Donna Bucci ◽  
...  
Keyword(s):  
Respiratory Failure ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Rapid Screening ◽  
Induction Treatment ◽  
High Dose ◽  
Protein Chain ◽  
Consolidation Therapy ◽  
Newly Diagnosed ◽  
Early Results

Abstract Among the prognostic cytogenetic and molecular aberrations in AML, t(8;21)(q22;q22) and inv(16)(p13q22) and their corresponding molecular rearrangements RUNX1/RUNX1T1 and CBFB/MYH11 (each involving a gene encoding a protein chain of the key transctiption factor CBF), predict for a favorable outcome in pts receiving consolidation with high-dose cytarabine (HiDAC) after achievement of complete remission (CR). However, approximately 40% of these pts eventually relapse. Approximately 25% of CBF AML pts carry gain-of function mutations in the KIT gene. These mutations result in a constitutively active tyrosine kinase (TK) that contributes to aggressive leukemia growth, and is associated with unfavorable outcome. In addition, CBF AML pts with wild type KIT overexpress this protein, and this is also associated with an inferior outcome. Therefore, inhibiting KIT with DAS is a rational therapeutic strategy in CBF AML. We report here on a phase II trial that combined DAS with standard chemotherapy for CBF AML. Enrollment required molecular confirmation of CBF AML by the Alliance Molecular Pathology central lab using RT-PCR and Sanger sequencing-based assays. Overall, 779 patients were screened for CBF; 69 were found to be CBF-positive and 61 were subsequently enrolled. Newly diagnosed RUNX1/RUNX1T1 or CBFB/MYH11-positive pts received induction chemotherapy with cytarabine (C) 200 mg/m2/day continuous intravenous (IV) infusion on days 1-7, daunorubicin (DNR) 60 mg/m2/d IV bolus on days 1-3 and DAS 100 mg/d PO on days 8-21. Pts with residual disease (>5% blasts) on day 21 after first induction received a re-induction treatment with same doses of C on days 1-5, DNR on days 1-3 and DAS on days 6-19. Pts who achieved CR received consolidation therapy with HiDAC 3000 mg/m2 over 3 hours (if <60 yrs old) or 1000 m/m2 (if older) q12h on days 1,3,5 and DAS 100 mg/d PO on days 6-26 x 4 courses. Pts who remained in CR after consolidation treatments received continuation treatment with DAS 100mg/d PO x 12 months. The primary goal of this study was to insure that the CR rate and survival during induction were not inferior to historical outcomes. Between April 2011 and January 2013, we completed the planned accrual of 61 adult CBF AML pts. Median age was 51 years (yrs; range: 19.6 to 85 yrs), and 15 pts (24%) were older (>60 yrs). Half of pts were male (51%) and a majority were Caucasian (75%). Of all 61 pts, 65% were CBFB/MYH11-positive and 35% were RUNX1/RUNX1T1-positive. Treatment was started on average 4 days from molecular diagnosis (range: 0 to 11 days). To date, 51% of pts are still undergoing treatment; 4 pts died on treatment (2 older), 7 (4 older) had an adverse event requiring treatment interruption, and 6 refused to complete the treatment (mainly the continuation component). Observed toxicities were those expected with C and DNR (hematologic and non-hematologic) and with DAS (nausea, liver toxicity). 55 pts are currently evaluable for treatment-related toxicity. The most common grade 4 toxicities were sepsis (5), acute kidney injury (3), and respiratory failure (3). Grade 5 toxicities included respiratory failure (1) and sepsis (2). Two of these pts died during induction (respiratory failure, sepsis); both were older and CBFB/MYH11. One pt died from sepsis during consolidation in CR (CBFB/MYH11, 48 yrs). The 30-day survival rate was 97% (95% CI: 89% to 99.6%) overall (98% in younger and 93% in older pts). Of 59 pts currently evaluable for response, 54 (92% of all pts; 96% younger and 80% older) achieved CR. Of the 5 patients who failed to achieve CR, 2 had RUNX1/RUNX1T1 and 3 had CBFB/MYH11. Among the 54 CR pts, no younger pt has relapsed, while 2 older pts with CBFB/MYH11 have relapsed. The median follow-up (f/u) was 11.2 months (range: 1.2 to 23.2 mos.). The 1-yr DFS and OS rates were respectively 90% and 87% for all pts; 97% and 95% for younger pts, and 63% and 62% for older pts, respectively. Early results from this study show that 1) rapid screening for CBF AML is feasible within a cooperative group, 2) DAS plus chemotherapy in CBF AML pts is tolerable including in older pts, and 3) the initial clinical outcomes are at least comparable to those historically observed in this patient population. Patients continue to be followed for survival endpoints. Molecular characterization for KIT mutations and expression levels of marrow and blood blasts is ongoing and will be correlated with toxicity and clinical outcome. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Final Results of the AML12 Trial of the Spanish Cetlam Group in Adults with Acute Myeloid Leukemia (AML) up to the Age of 70 Years: Risk Adapted Post-Remission Allocation Based on Genetic Data and Minimal Residual Disease

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 289-289
Author(s):  
Jorge Sierra ◽  
Ana Garrido ◽  
Marina Diaz Beya ◽  
Montserrat Hoyos ◽  
Marisa Calabuig ◽  
...  
Keyword(s):  
Minimal Residual Disease ◽  
Research Funding ◽  
Residual Disease ◽  
High Dose ◽  
Severe Toxicity ◽  
Group Setting ◽  
Npm1 Mutation ◽  
Allogeneic Hct ◽  
Molecular Features ◽  
Minimal Residual

BACKGROUND: AML risk classification is based on genetics (cytogenetics and molecular features) and more recently also on minimal residual disease (MRD) after chemotherapy. These two aspects allow predicting relapse and supporting or not the most anti-leukemia treatment that remains allogeneic hematopoietic cell transplantation (HCT). We prospectively investigated the combined use of the two predictive markers to allocate post-remission therapy with or without HCT. Objectives of the study were testing: a) if this approach was feasible in a multicenter setting; b) the proportion of patients who were allocated to an allogeneic HCT and finally received the procedure; c) the final distribution into the risk categories and their outcome; d) to analyze the outcome of patients with favorable or intermediate genetics moved to the high risk category because of positive MRD. METHODS: Adult patients with primary AML treated at 15 academic hospitals were included between February 2012 and December 2018. Induction chemotherapy consisted of idarubicin 12 mg/m2 days 1-2-3 and cytarabine 200 mg/m2 days 1 to 7. Consolidation courses were high-dose cytarabine (3 g/m2 or 1.5 g/m2 if ≥60 y/o). The number of consolidation courses was based on genetic risk: 3 in favorable genetics category (FGC) (CBF, NPM1mut/FLT3-ITDwild or ratio&lt;0.5, and CEBPA biallelic mutation); and one in the intermediate genetics category (IGC), including intermediate cytogenetics without favorable or unfavorable (FLT3-ITD, MLL, EVI1) molecular features, as well as in adverse genetics category (AGC). Following, the mandatory option was allogeneic HCT in the AGC and in the other genetic categories when MRD was positive. In the IGC without MRD autologous or HLA preferentially matched allogeneic HCT was a center decision. MRD was assessed by flow (positive &gt;0.1%) and/or quantitative PCR of the specific transcripts (RUNX1/RUNX1T1, CBFβ/MYH11 and NPM1). RESULTS: Seven hundred forty-five patients (median age: 55, range18-70 y/o, 51% male) were enrolled. Cytogenetics according the revised MRC classification in 707 informative cases was: CBF AML 12%, intermediate 65% (75% of them normal karyotype), and adverse 23%. FLT3-ITD was detected in 28% of patients with intermediate risk cytogenetics and NPM1 mutation in the same group was present in the 48%. Complete remission (CR) was achieved in 81% (n=603) of patients, 82% and 80% in patients up to and above 60 yrs, respectively. Induction death occurred in 9% of patients, 7% and 11% the two age groups, and 10% of patients had refractory leukemia; 542 (90%) of the 603 CR patients completed the consolidation phase and were risk allocated taking into account genetics and MRD. The remaining CR patients were not allocated because of early relapse (n=22), death in CR (n=5), severe toxicity (n=22) or others (n=12). After risk allocation, 208 (38%) patients were in the genetics-MRD combined favorable group (CFG), 103 (19%) in combined intermediate group (CIG) and 231 (43%) in the combined adverse group (CAG). In the latter, 185 (80%) of patients received an allogeneic HCT in first CR. Fifty-seven patients (11%) moved from the genetically FGC or IGC to the CAG because of high MRD at the end of consolidations. Median follow-up in survivors was 25 months. Overall 4-years survival (OS) of the whole series is 48±2%; event-free survival (EFS) is 77+3% in the CFG group, 45+6% in the CIG and 34+4% in the CAG (p&lt;0.001) due to difference in the cumulative relapse incidence (19%, 38% and 45%, respectively, p&lt;0.001 ). In the 57 patients who were MRD positive at the end of consolidation (FGC and IGC) had an OS of 53±8% and EFS of 45±7% at 4 years. CONCLUSION Risk adapted therapy for primary AML based on genetics and MRD is feasible in a cooperative group setting. The proportion of CR was high (&gt;80%) even in patients older than 60 y/o. MRD assessment at the end of consolidation moved 57 patients with favorable or intermediate genetics to the CAG. Avoiding HCT in first CR in the FGC patients associated to EFS above 75% at 4 years. Allogeneic transplantation feasibility was 80% when this was the intended treatment because of adverse genetics and/or MRD positivity. Risk assessment based on genetics and MRD continues separating three groups of patients with different outcomes. Since relapses remain frequent when adverse AML features are present, further approaches after transplantation, such as targeted agents and immune therapies deserve investigation. Disclosures Sierra: Astellas: Honoraria; Pfizer: Honoraria; Daiichi-Sankyo: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau; Roche: Honoraria; Jazz Pharmaceuticals: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau. Salamero:Daichii Sankyo: Honoraria; Pfizer: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Esteve:Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy; Daiichi Sankyo: Consultancy; Roche: Consultancy; Astellas: Consultancy, Speakers Bureau; Pfizer: Consultancy.

Oral Etoposide for Refractory and Relapsed Neuroblastoma

1999 ◽  
Vol 17 (10) ◽  
pp. 3221-3225 ◽  
Author(s):  
Brian H. Kushner ◽  
Kim Kramer ◽  
Nai-Kong V. Cheung
Keyword(s):  
Residual Disease ◽  
Alkylating Agents ◽  
High Dose Chemotherapy ◽  
Treatment Programs ◽  
Induction Treatment ◽  
High Dose ◽  
Oral Etoposide ◽  
Disease Markers ◽  
Stage 4 ◽  
Dose Oral

PURPOSE: To describe the efficacy of oral etoposide against resistant stage 4 neuroblastoma. PATIENTS AND METHODS: Patients with refractory or recurrent stage 4 neuroblastoma were treated with etoposide 50 mg/m2 taken orally each day, in two or three divided doses, for 21 consecutive days. Treatment could be repeated after a 1-week period. Extent-of-disease studies included imaging with 131-iodine-metaiodobenzylguanidine and extensive bone marrow (BM) sampling. RESULTS: Oral etoposide was used in 20 children between the ages of 2 and 11 years (median, 6 years). Prior treatment included high doses of alkylating agents and a median of 4.5 cycles of etoposide-containing chemotherapy, with cumulative etoposide doses of 1,800 mg/m2 to 3,935 mg/m2 (median, 2,300 mg/m2). Oral etoposide produced antineuroblastoma effects in four of four children with disease refractory to intensive induction treatment; sampling variability could account for resolution (n = 3) or reduction (n = 1) of BM involvement, but improvement in other markers also occurred. Antineuroblastoma effects were also evident in five of five children with asymptomatic relapses after a long chemotherapy-free interval: BM disease resolved and all other disease markers significantly improved in two patients, and disease markers improved or stabilized in three patients on treatment for more than 6 months. In these nine patients, extramedullary toxicity was absent, neutropenia did not occur, transfusional support was not needed, and preliminary data suggested little immunosuppression (phytohemagglutinin responses). Oral etoposide was ineffective in all (11 of 11) patients with rapidly growing tumor masses. CONCLUSION: Given the absence of toxicity to major organs, the minimal myelosuppression or immunosuppression, and the antineoplastic activity in patients with low tumor burdens after high-dose chemotherapy, limited use of low-dose oral etoposide should be considered for inclusion in postinduction consolidative treatment programs aimed at eradicating minimal residual disease.

scholarly journals Interleukin-2 may induce prolonged remissions in advanced acute myelogenous leukemia

Blood ◽  
1994 ◽  
Vol 84 (7) ◽  
pp. 2158-2163 ◽  
Author(s):  
G Meloni ◽  
R Foa ◽  
M Vignetti ◽  
A Guarini ◽  
S Fenu ◽  
...  
Keyword(s):  
Acute Myelogenous Leukemia ◽  
Residual Disease ◽  
Therapeutic Option ◽  
Interleukin 2 ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Antileukemic Effect ◽  
Acute Myelogenous ◽  
History Of

Abstract The administration of interleukin-2 (IL-2) may induce complete remissions in acute myelogenous leukemia (AML) patients with a low proportion of residual bone marrow (BM) blasts. To confirm this preliminary observation, we treated 14 AML patients with advanced disease and with a residual BM blastosis that ranged between 7% and 24% with repeated 5-day cycles of high-dose recombinant IL-2 administered by daily continuous intravenous infusion. Patients who responded have been subsequently submitted to a monthly maintenance scheme with subcutaneous IL-2 at lower doses. While using this schedule and closely monitoring clinical and laboratory conditions, side effects were acceptable and no toxic deaths recorded. Eight of the 14 patients treated with high-dose IL-2 obtained a complete remission (CR). Five remain in persistent CR (four in third CR and one in fourth CR) after a median follow-up time of 32 months (14, 30, 32, 33, and 68 months, respectively). In all five patients, the IL-2-induced remission is the longest in the natural history of the disease. These findings show that IL-2 displays an antileukemic effect in AML with limited residual disease, and suggest that IL-2 should be considered a therapeutic option for resistant or relapsed AML patients.

Peripheral Blood Stem Cell (PBSC) Harvest Is More Expensive Following Bortezomib-Based Therapy in Multiple Myeloma (MM), Related to Increase Number of Days of Collect.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1373-1373
Author(s):  
Matthieu Barthelemy ◽  
Florence Boulanger ◽  
Houria Debarri ◽  
Laurent Pascal ◽  
Pierre Samarcq ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Induction Therapy ◽  
Young Patients ◽  
Standard Of Care ◽  
Induction Treatment ◽  
High Dose ◽  
Front Line ◽  
History Of ◽  
The Cost

Abstract Abstract 1373 Poster Board I-395 Background: High-dose therapy is the front line treatment of reference in young patients with Multiple Myeloma (MM). Although induction therapy remains a matter of controversy, bortezomib-based therapy is considered more and more as a standard of care. Prior to autologous stem cell transplantation (ASCT), patients undergo PBSC collect, usually starting after cycle 2 to 4 of the induction treatment. Currently, patients receive one transplant at front line, but most of the patients will benefit throughout the MM disease history of a second or a third ASCT procedure. We have noticed that the number of days of collection vary from patient-to-patient following bortezomib-based induction therapy. This increase in collection procedures might increase the cost of PBSC harvest with more patients discomfort and staff unavailability. We have therefore further studied the quality, yields and days of collection in myeloma patients following bortezomib-based therapy as compared to other regimens-based treatment courses. Material and Method: We retrospectively studied 70 patients with myeloma that underwent PBSC harvestsafter mobilization with GCSF following debulking with bortezomib-based therapy (58 days of procedures – 26 patients) versus other agents-based therapy [65 days of procedure – 44 patients; VAD vincristine, adriamycin, dexamethasone). Results: -Yields. CD34 Mobilization is lower following bortezomib-based therapy as compared to other regimen-based therapy. Similarly, more days of collection are also needed to collect the requested yield of PBSC. -Engrafment. No significant differences regarding engraftment was noticed among the 2 groups studied. The days to neutrophil and platelet counts recovery, the number of days with fever and the number of red cell and platelet transfusions were not significantly different between the 2 groups, mobilization following bortezomib-based therapy versus other regimen-based therapy, respectively. Conclusion: In our series, bortezomib-based induction regimen does not increase the number of PBSC harvest failure and the quality of engraftment was identical to other regimen-based induction treatment. However, CD34 mobilization was lower following bortezomib-based therapy, which explains lower daily harvest counts and therefore an increase number of days of collection in bortezomib-based treated patients. Therefore, PBSC harvest procedure following bortezomib-based therapy significantly increases the cost of PBSC collection. These results need to be confirmed in larger studies. New agents in use for mobilization might be considered for future PBSC collection in bortezomib-based treated patients. Disclosures: Leleu: Janssen Cilag: Research Funding.

Analysis of Immunophenotypic Response (IR) by Multiparameter Flow Cytometry In 516 Myeloma Patients Included In Three Consecutive Spanish Trials

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1910-1910 ◽  
Author(s):  
Bruno Paiva ◽  
María-Belén Vidriales ◽  
María-Angeles Montalbán ◽  
María-Victoria Mateos ◽  
Laura Rosiñol ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Board Of Directors ◽  
Residual Disease ◽  
Young Patients ◽  
Novel Agents ◽  
Multiparameter Flow Cytometry ◽  
High Dose ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
The Impact

Abstract Abstract 1910 The outcome of multiple myeloma (MM) patients has markedly improved in the last decade. Thus, overall response rates between 85%-95%, with 30%-50% complete remission (CR) rates are now being reported in young patients treated with novel agents plus high-dose therapy/autologous stem cell transplantation (HDT/ASCT). A similar scenario is also emerging in the elderly (non-transplant candidates) population. Accordingly, more sensitive techniques are needed to assess patients’ response; these may contribute to compare the efficacy of different treatment schemas, to monitor minimal residual disease (MRD) and for prognostication. In the present study we have assessed the frequency and the prognostic value of IR by multiparameter flow cytometry in a total of 516 newly diagnosed MM patients included in three consecutive PETHEMA/GEM Spanish trials: two designed for transplant candidate patients - GEM 2000 (n=157) and GEM2005<65y (n=206) - and one for elderly patients - GEM2005>65y (n=153). The GEM2000 trial was based on 6 induction cycles of VBMCP/VBAD followed by HDT/ASCT; the GEM2005<65y included three arms with 6 cycles each (Thalidomide/Dexamethasone -TD-, Bortezomib/Thalidomide/Dexamethasone -VTD- and, VBMCP/VBAD with Bortezomib in the two final cycles -VBMCP/VBAD/Bortezomib) followed by HDT/ASCT; and the GEM2005>65y compared 6 cycles of Bortezomib/Melphalan/Prednisone -VMP- vs. Bortezomib/Thalidomide/Prednisone -VTP-. All three trials had in common that patients received 6 induction cycles and IR was evaluated at this time point. In addition, IR was assessed on day +100 after HDT/ASCT in the first two trials. Patients were defined to be in IR when myelomatous plasma cells (MM-PCs) were undetectable by MFC or when less than one phenotypically aberrant PC was detected among 104 cells analyzed. Patients were referred for MRD studies if they were mainly in CR or VGPR. The IR rates reported here were calculated on intention to treat analysis. Figure 1 summarizes the IR rates after induction. The lowest IR rates corresponded to the VBMCP/VBAD and TD schemes (5% and 6%, respectively) while with the bortezomib-based regimens an approximately 3-fold increment in the IR rates was observed: VTP (12%), VBMCP/VBAD/Bortezomib (15%), VMP (16%) and VTD (17%). After HDT/ASCT, IR rates were found to be significantly increased (p<.001) in the GEM2000 protocol (14%) and in all arms of the GEM2005<65y trial: TD (18%), VBMCP/VBAD/Bortezomib (30%) and VTD (34%). Thus, a minimum 2-fold increment of IR rates was further achieved after HDT/ASCT. In addition, IR rates achieved after HDT/ASCT in patients included in all three arms of the GEM2005<65y trial were significantly superior (p≤.008) to cases treated according to the GEM2000 protocol, indicating that induction regimens with novel agents improved post-transplantation rates of IR. Moreover, bortezomib-based regimens vs. TD were associated with increased IR rates not only before but also after HDT/ACSCT (p=.06 and p=.02 for VBMCP/VBAD/Bortezomib and VTD, respectively). We further compared the impact of achieving an IR after induction and at day+100 after HDT/ASCT in the progression-free (PFS) and overall survival (OS) within the three protocols. Patients in IR status after an induction regimen according to the GEM2000, GEM2005<65y and GEM2005>65y protocols showed significantly longer (p<.001) 3-year PFS rates (100%, 100% and 90%, respectively) compared to patients in a no-IR status (61%, 59% and 35%, respectively). Similarly, 3-year OS rates were significantly longer (p=.01) in IR vs. no-IR patients status (100%, 100% and 94% vs. 84%, 90% and 76% for the GEM2000, GEM2005<65y and GEM05>65y protocols, respectively). Likewise, an IR vs. no-IR status after HDT/ASCT in both the GEM2000 and GEM05<65y trials was also associated with significantly increased 3-year PFS (p<.001) and OS (p=.007) rates. In summary, this study demonstrates that the achievement of an IR is a strong prognostic factor regardless of the type of treatment; thus, higher IR rates may help to identify optimal therapeutical schemes. In this sense, HDT/ASCT is able to markedly increase IR rates after induction even in the era of novel agents, and this translates into extended survival. Disclosures: Off Label Use: VTP is not approved for the treatment of newly diagnosed myeloma patients and VT and VP are not approved for maintenance therapy. None of the combinations proposed, VBCMP/VBAD plus bortezomib, VT and VTD are approved as induction therapy in newly diagnosed myeloma patients. Mateos:Janssen Cilag: Honoraria; Celgene: Honoraria. Rosiñol:Janssen-Cilag: Honoraria; Celgene: Honoraria. Cibeira:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Oriol:Janssen-Cilag: Honoraria; Celgene: Honoraria. de Arriba:Janssen-Cilag: Honoraria; Celgene: Honoraria. Palomera:Janssen Cilag: Honoraria. De La Rubia:Janssen-Cilag: Honoraria; Celgene: Honoraria. Díaz-Mediavilla:Janssen-Cilag: Honoraria; Celgene: Honoraria. Garcia-Laraña:Janssen Cilag: Honoraria; Celgene: Honoraria. Sureda:Janssen-Cilag: Honoraria; Celgene: Honoraria. Alegre:Janssen-Cilag: Honoraria; Celgene: Honoraria. Blade:Janssen cilag: Honoraria; Celgene: Honoraria. Lahuerta:Janssen-Cilag: Honoraria; Celgene: Honoraria. San Miguel:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Results of the ECOG E1900 Trial in Younger Adults with AML Using an Event Free Survival Endpoint Are Concordant with Results Based on Overall Survival: Potential for a Surrogate Endpoint to Facilitate Rapid Approval of Therapies in AML

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2599-2599 ◽  
Author(s):  
Marlise R. Luskin ◽  
Ju-Whei Lee ◽  
Hugo F. Fernandez ◽  
Hillard M. Lazarus ◽  
Jacob M. Rowe ◽  
...  
Keyword(s):  
Overall Survival ◽  
Clinical Trials ◽  
Treatment Failure ◽  
Induction Treatment ◽  
High Dose ◽  
Event Free Survival ◽  
Npm1 Mutation ◽  
Free Survival ◽  
The Impact

Abstract Background: Novel therapies are required to improve the outcome of patients with AML. New agents are asked to demonstrate an overall survival (OS) benefit before qualifying for FDA approval. The long duration of clinical trials required in order to achieve this endpoint hampers quick evaluation of candidate therapies, including novel agents. Identification of reliable surrogate endpoints for OS in AML is needed. Here we compare the results of therapy for patients with untreated AML ages 16-60 years on the Eastern Cooperative Oncology Group 1900 trial (E1900) of induction chemotherapy followed by consolidation and autologous transplant in order to evaluate the validity of an event free survival (EFS) endpoint as a surrogate for OS. Methods:OS was measured from randomization for induction therapy to death from any cause (censored at last contact). EFS was measured from randomization to induction treatment failure, relapse after compete response (CR), or death in remission (censored at last contact). Hazard ratios (HR) were computed using Cox proportional hazards models. The association between EFS and OS was evaluated using the Kendall tau-a rank correlation for censored data. Results:There were657 patients enrolled of which 426 patients relapsed or had induction treatment failure before death or date of last contact. Median EFS and OS were 8.0 months (95% CI, 6.3 to 9.7 months) and 23.6 months (95% CI, 16.9 to 23.6 months), respectively. With a median follow-up of 80.1 months, there is a statistically significant correlation between EFS and OS (Kendall tau-a = 0.467, 95% confidence interval (CI) = (0.425, 0.510), p<0.001). This correlation was similarly significant at a median follow-up of 25.2 months (Kendall tau-a = 0.361, 95% CI (0.323, 0.400), p <0.001) when the E1900 trial was originally reported (Fernandez et al. NEJM 2009). Key findings reported based on the original OS endpoint are similar when analyzed with an EFS endpoint (Table 1). High-dose daunorubicin (90 mg/m2) (DNR 90) confers both an EFS and OS benefit in patients aged < 50 years and patients with intermediate cytogenetic risk, and does not confer an EFS or OS benefit in older patients and patients with unfavorable cytogenetic risk, on univariate analysis. Divergent results are only seen in the small subset of favorable cytogenetic risk patients, where DNR 90 conferred an OS benefit (p=0.027) without an EFS benefit (p=0.32). Both EFS and OS endpoints consistently reflect the impact of mutation status on survival. The presence of a FLT3-ITD or DNMT3A mutation has a negative impact on both EFS and OS while an IDH2 mutation has a favorable impact on EFS and OS. The presence of a NPM1 mutation confers a favorable impact on EFS and OS in patients who received DNR 90 and did not impact EFS or OS in patients receiving standard-dose daunorubicin (45 mg/m2) (DNR 45). The presence of an IDH1 mutation does not impact EFS or OS. Conclusions:The results of E1900 demonstrating superiority of DNR 90 in AML induction in patients up to age 60 are concordant when using an EFS or OS endpoint. This is true for the group as a whole as well as for subgroups for which targeted agents are in development (FLT3/IDH2 inhibitors). Further investigation of whether EFS is a reliable surrogate for OS is warranted in AML. If confirmed, its use as a primary endpoint could be adopted by regulatory agencies in order to allow more rapid completion of clinical trials in AML and bring new therapies to AML patients in a timely fashion. Table 1. Results of E1900 based on an EFS endpoint versus an OS endpoint. Subgroup N OS HR (DNR 90/DNR 45) & 95% CI Wald P EFS HR (DNR 90/DNR 45) & 95% CI Wald P DNR 45 DNR 90 Age < 50 yrs ³ 50 yrs 188 142 172 155 0.66 (0.50, 0.85) 0.81 (0.62, 1.06) 0.002 0.118 0.64 (0.50, 0.82) 0.86 (0.67, 1.10) 0.0004 0.23 Cytogenetic Favorable Intermediate Unfavorable 38 141 59 51 127 63 0.51 (0.28, 0.93) 0.68 (0.50, 0.92) 0.79 (0.54, 1.16) 0.027 0.012 0.225 0.76 (0.44, 1.31) 0.63 (0.47, 0.83) 0.72 (0.49, 1.05) 0.32 0.001 0.09 Subgroup N OS HR (MUT/WT) & 95% CI Wald P EFS HR (MUT/WT) & 95% CI Wald P FLT3-ITD WT MUT 456 147 1.62 (1.31, 2.01) <.0001 1.48 (1.21, 1.82) 0.0002 DNMT3A WT MUT 371 119 1.30 (1.03, 1.65) 0.03 1.23 (0.98, 1.54) 0.07 IDH1 WT MUT 465 36 0.88 (0.59, 1.33) 0.55 0.91 (0.62, 1.34) 0.64 IDH2 WT MUT 451 50 0.63 (0.43, 0.93) 0.02 0.68 (0.48, 0.97) 0.03 NPM1 DNR 45 DNR 90 245 257 0.84 (0.61, 1.16) 0.60 (0.41, 0.89) 0.30 0.01 0.90 (0.66, 1.22) 0.59 (0.41, 0.84) 0.49 0.004 Disclosures No relevant conflicts of interest to declare.

scholarly journals Efficacy of Rituximab in a Systemic Lupus Erythematosus Patient Presenting with Diffuse Alveolar Hemorrhage

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Gabriela Montes-Rivera ◽  
Grissel Ríos ◽  
Luis M. Vilá
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Therapeutic Option ◽  
Acute Onset ◽  
Diffuse Alveolar Hemorrhage ◽  
Alveolar Hemorrhage ◽  
High Dose ◽  
Systemic Lupus ◽  
Effective Therapeutic Option ◽  
Life Threatening

Diffuse alveolar hemorrhage (DAH) is a life-threatening complication of systemic lupus erythematosus (SLE). Although infrequent, its mortality is very high. While there are no established therapeutic guidelines, DAH has been traditionally managed with high-dose intravenous (IV) corticosteroids, cyclophosphamide, and plasma exchange. The efficacy of alternative therapies such as rituximab has been described only in a few cases. Herein, we report a 25-year-old Hispanic man who presented with acute-onset SLE manifested by polyarthralgia, nephritis, seizures, pancytopenia, severe hypocomplementemia, and elevated anti-dsDNA antibodies. His disease course was complicated by DAH. His condition was refractory to high-dose intravenous (IV) methylprednisolone pulses, IV cyclophosphamide, and plasmapheresis. Given the lack of clinical response, he was started on IV rituximab 375 mg/m2 weekly for a total of four courses. He rapidly improved after the first two doses. Over the next seven months, he did not present recurrent pulmonary symptoms. Follow-up chest computed tomography did not show residual abnormalities. This case, together with other reports, suggests that rituximab is an effective therapeutic option for DAH in SLE.

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